Novel tripeptides, intermediates therefor and pharmaceutical compositions and methods employing said tripeptides

ABSTRACT

Novel tripeptides having the following amino acid sequence 
     
         H-Tyr-X-Gly-Y 
    
     wherein: X is a chiral residue of a D-amino acid selected from the group consisting of D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-proline D-aspartic acid, D-asparagine, D-lysine, D-arginine and D-histidine; and Y is selected from the group consisting of hydroxy, amino, loweralkylamino, diloweralkylamino and lower alkoxy; and the pharmaceutically acceptable salts thereof; intermediates useful in making the novel compounds; and pharmaceutical compositions and methods employing the novel compounds.

BACKGROUND OF THE INVENTION

While there are a number of analgesic agents currently utilized torelieve mild to severe pain, the search for improved analgesics is acontinuing one because of the numerous problems associated with thepresently available agents. Aspirin and related salicylates areconsidered to be non-narcotic analgesic agents useful for relieving mildto moderate pain in addition to their usefulness as anti-inflammatoryand anti-pyretic agents. However, the ingestion of salicylic acid orrelated salicylates may result in epigastric distress, nausea andvomiting. This widely used class of non-narcotic analgesic agents mayalso cause gastric ulceration and even hemorrhage both in experimentalanimals and man. Exacerbation of peptic ulcer symptoms and erosivegastritis have all been reported in patients on high dose therapy, i.e.,arthritis patients. Aspirin is also one of the most common causes ofdrug poisoning in young children and has a potential of serious toxicityif used improperly.

Acetaminophen is also considered to be a non-narcotic analgesic agentuseful in treating mild pain associated with simple headache, commonmuscular aches, etc. While acetaminophen is particularly useful forpatients who cannot take aspirin, e.g., ulcer patients, its use iscontraindicated in individuals who have exhibited a sensitivity to it.In addition to their drawbacks in view of their potential side effects,the mild non-narcotic analgesic agents are not sufficiently potent torelieve the severe pain associated with surgery, cancer and the like.

Unfortunately, the potent analgesic agents capable of relieving suchsevere pain are also narcotic agents and their use entails the risk ofproducing physical or psychological dependence. There are as yet noagents effective against severe pain that are entirely free of thisrisk.

Thus, there is an urgent need for improved analgesic agents for treatingmild as well as severe pain. The present invention provides such agents.

In addition to the need for improved analgesic agents, there is also aneed for improved psychotropic agents to replace or to provide analternative to current therapy. The compounds of this invention, inaddition to their analgesic activity, also exhibit anti-depressant,tranquilizing, sedative and hypnotic activity. Thus, their usefulness asanalgesic agents is enhanced, since many patients suffering from painalso exhibit varying states of anxiety and depression.

A recently identified pentapeptide, methionine enkephalin, has thefollowing structure H-Tyr-Gly-Gly-Phe-Met-OH [see Hughes et al., Nature,258, 577 (1975)]. This peptide is found in many areas of the brain whereit appears to act as a neurotransmitter or neuromodulator in a centralpain suppressive system. The natural peptide binds stereo-specificallyto partially purified brain opiate receptor sites [for instance, seeBradbury et al., Nature, 260, 793 (1976)], is very active in bioassaysfor opiate activity, but exhibits only weak analgesic agent of shortduration when injected directly into the brain of the rat, [forinstance, see Belluzzi et al., Nature, 260, 625 (1976)].

In addition, several C-terminal fragments of a 91 chain length peptide,of mammalian β-lipotropin having the pentapeptide sequence of methionineenkephalin at their N-terminus have been isolated from the pituitary andfound to exhibit potent opioid activity in binding to partially purifiedbrain opiate receptor sites. [See Ling and Guillemin, Proc. Natl. Acad.Sci. USA 73, 3308 (1976) and Proc. Natl. Acad. Sci. USA 73, 1821(1976)]. The reported fragments have been characterized as α-endorphin(β-lipotropin fragment 61-76), β-endorphin (β-lipotropin fragment61-91), γ-endorphin (β-lipotropin fragment 61-77) and δ-endorphin(β-lipotropin fragment 61-87), β-LPH-[61-68], β-LPH[61-79], β-LPH[61-69]and β-LPH[61-64]. [See also Lazarus et al., Proc. Natl. Acad. Sci. USA,Vol. 73, No. 6, pp. 2156-2159 June 1976)].

Thus far, β-lipotropin or the above fragments thereof have been isolatedfrom pituitary of various mammals such as rat, dog, pig, camel, sheepand human pituitary tissue.

This invention is directed to novel derivatives of mammalianβ-lipotropin fragment 61-63.

SUMMARY OF THE INVENTION

This invention relates to novel peptides, and more specifically relatesto novel derivatives of mammalian β-lipotropin fragment 61-63 which areuseful as analgesic, tranquilizer, sedative, hypnotic, anti-depressantprolactin releasing and growth hormone releasing agents, tointermediates useful in the preparation of the novel tripeptides, and topharmaceutical compositions and methods employing such noveltripeptides.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The compounds of this invention are tripeptides represented by formula Iand having the following amino acid sequence:

    H-Tyr-X-Gly-Y                                              (I)

wherein: X is a chiral residue of a D-amino acid selected from the groupconsisting of D-alanine, D-leucine, D-isoleucine, D-valine,D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine,D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-proline,D-asparagine, D-lysine, D-arginine and D-histidine; and Y is selectedfrom the group consisting of hydroxy, amino, aminoloweralkyl,aminodiloweralkyl, or lower alkoxy; and the pharmaceutically acceptablesalts thereof.

All chiral amino acid residues identified herein are in the natural orL-configuration unless otherwise specified.

In keeping with standard peptide nomenclature, abbreviations for chiralamino acid residues have been used herein as follows:

    ______________________________________                                        Tyr                                                                           L-tyrosine            Ile                                                     L-isoleucine                                                                  D-Tyr                                                                         D-tyrosine                                                                           D-Ile                                                                  D-isoleucine                                                                  Gly                                                                           glycine                                                                              Leu                                                                    L-leucine                                                                     Phe                                                                           L-phenylalanine                                                                      D-Leu                                                                  D-leucine                                                                     D-Phe                                                                         D-phenylalanine                                                                      Thr                                                                    L-threonine                                                                   Met                                                                           L-methionine                                                                         D-Thr                                                                  D-threonine                                                                   D-Met                                                                         D-methionine                                                                         Val                                                                    L-valine                                                                      Ala                                                                           L-alanine                                                                            D-Val                                                                  D-valine                                                                      D-Ala                                                                         D-alanine                                                                            Pro                                                                    L-proline                                                                     Ser                                                                           L-serine                                                                             D-Pro                                                                  D-proline                                                                     D-Ser                                                                         D-serine                                                                             Gln                                                                    L-glutamine                                                                   Lys                                                                           L-lysine                                                                             D-Gln                                                                  D-glutamine                                                                   D-Lys                                                                         D-lysine                                                                             Glu                                                                    L-glutamic acid                                                               Asn                                                                           L-asparagine                                                                         D-Glu                                                                  D-glutamic acid                                                               D-Asn                                                                         D-asparagine                                                                         Trp                                                                    L-tryptophan                                                                  His                                                                           L-histidine                                                                          D-Trp                                                                  D-tryptophan                                                                  D-His                                                                         D-histidine                                                                          D-Asp                                                                  D-aspartic acid                                                               ______________________________________                                    

The term "pharmaceutically acceptable salts," as used herein, refers tothe non-toxic alkali metal, alkaline earth metal and ammonium saltscommonly used in the pharmaceutical industry including the sodium,potassium, lithium, calcium, magnesium, barium and ammonium salts whichare prepared by methods well known in the art. The term also includesnon-toxic acid addition salts which are generally prepared by reactingthe compounds of this invention with a suitable organic or inorganicacid. Representative salts include the hydrochloride, hydrobromide,sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, napsylate, and the like.

The term "lower alkyl" refers to straight and branched chain alkylgroups having from 1 to 6 carbon atoms, such as ethyl, n-propyl,iso-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl,1,2-dimethylbutyl, and the like.

The term "lower alkoxy" refers to straight and branched chain alkoxygroups having from 1 to 6 carbon atoms such as methoxy, ethoxy, and thelike.

Also contemplated within the scope of the present invention are thefollowing intermediates which are useful in preparing the tripeptides ofthis invention and are represented by Formula II.

    r.sub.1 -tyr(R.sub.2)-X'-Gly-Y                             (II)

wherein

X' is equal to X as defined in Formula I above, except in the case ofD-threonine, D-serine, D-tyrosine, D-glutamic acid, D-arginine,D-asparagine and D-lysine in which cases X' is a chiral residue of aD-amino acid as defined in Formula I protected by an R₂, R₃, R₄, R₅, R₆protecting group as defined below:

R₁ is a solid state peptide synthesis N-terminus protecting groupselected from the group consisting of acyl type protecting groups,aromatic urethan-type protecting groups, alkyl type protecting groups,trialkylsilane groups, or aliphatic urethan protecting groups;

R₂ is a protecting group for the phenolic hydroxyl group of tyrosineselected from the group consisting of tetrahydroproponyl, tert-butyl,trityl, benzyl, 2,4-dichlorobenzyl, benzyloxycarbonyl or2-bromobenzyloxycarbonyl (2-BrZ);

R₃ is a protecting group for the alcohol hydroxy functions of serine andthreonine, selected from the group defined above for R₂ ;

R₄ is a protecting group for the gamma carboxyl group of glutamic acidselected from the group consisting of tert-butyl, benzyl, and4-chlorobenzyl;

R₅ is a protecting group for the epsilon amino group of lysine selectedfrom the group consisting of trifluoroacetyl, benzyloxycarbonyl or,preferably, 2-chlorobenzyloxycarbonyl; and

R₆ is a protecting group for the guanidine group of arginine and isselected from the group of nitro or tosyl.

Y is as defined in Formula I above or a derivatized insolublepolystyrene resin support represented by Formulae III or IV: ##STR1##

The term "acyl-type protecting groups" refers to groups illustrated bybut not restricted to formyl, trifluoroacetyl, tosyl, nitrosulfonyl, andthe like.

The term "aromatic urethan-type protecting groups" is represented bygroups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-biphenylisopropyloxycarbonyl, 2,5-dimethoxyphenylisopropyloxycarbonyl,and the like.

The term "cycloalkyl urethan protecting group," as used herein, refersto groups such as cyclopentyloxycarbonyl, adamantyloxycarbonyl,cyclohexyloxycarbonyl, isobornyloxycarbonyl, etc.

"Alkyl type protecting groups" are those commonly used in the art suchas the trityl group.

"Trialkylsilane groups" include compounds such as trimethylsilane,triethylsilane, tributylsilane, and the like.

The preferred protecting groups, the "aliphatic urethan protectinggroups," include tert-butyloxycarbonyl, diisopropyloxycarbonyl,isopropyloxycarbonyl, allyloxycarbonyl, and the like.

The polystyrene resin support is preferably a copolymer of styrene with1-2 weight percent of divinyl benzene as a cross-linking agent whichcauses the polystyrene polymer to be completely insoluble in mostorganic solvents. In Formula IV, φ is phenyl.

In selecting a particular side-chain protecting group to be used in thesynthesis of the peptides, several conditions must be met: (a) theprotecting group must be stable to the reagent and under reactionconditions selected for removing the α-amino protecting group at eachstep of the synthesis; (b) the protecting group must retain itsprotecting properties and not be chemically modified; and (c) theside-chain protecting group must be removable at the end of thesolid-phase synthesis under reaction conditions that will not alter thepeptide chain.

The peptides are prepared using standard solid-phase techniques. Thesynthesis is commenced from the C-terminal end of the peptide using anα-amino protected resin. A suitable starting material can be prepared,for instance, by attaching the required α-amino acid to achloromethylated resin, a hydroxymethyl resin, or a benzhydrylamineresin. One such chloromethylated resin is sold under the tradenameBIO-BEADS SX-1 by Bio Rad Laboratories, Richmond, Calif. and thepreparation of the hydroxymethyl resin is described by Bodonszky et al.,Chem. Ind. (London) 38, 1597 (1966). The benzhydrylamine resin has beendescribed by Pietta and Marshall, Chem. Commun., 650 (1970) and iscommercially available from Beckman Instrument, Palo Alto, Calif.

In the preparation of the compounds of this invention, an α-aminoprotected amino acid is coupled to the chloromethylated resin with theaid of, for example, cesium bicarbonate catalyst, according to themethod described by Gisin, Helv, Chim. Acta, 56, 1476 (1973). After theinitial coupling, the α-amino protecting group is removed by a choice ofreagents including trifluoroacetic acid or hydrochloric acid solutionsin organic solvents at room temperature. After removal of the α-aminoprotecting group, the remaining protected amino acids are coupledstepwise in the desired order to obtain the compounds of Formula II.Each protected amino acid is generally reacted in a 3-fold excess usingan appropriate carboxyl group activator such as dicyclohexylcarbodiimidein solution in, for example, methylene chloride-dimethylformamidemixtures.

After the desired amino acid sequence has been completed, the desiredpeptide is removed from the resin support by treatment with a reagentsuch as hydrogen fluoride which not only cleaves the peptide from theresin, but also cleaves all remaining side-chain protecting groups. Whenthe chloromethylated resin is used, hydrogen fluoride treatment resultsin the formation of the free peptide acids of Formula I (Y=OH). When thebenzhydrylamine resin is used, hydrogen fluoride treatment resultsdirectly in the free peptide amides of Formula I (Y=NH₂). Alternatively,when the chloromethylated resin is employed, the side-chain protectedpeptide can be cleaved by treatment of the peptide-resin with ammonia togive the desired side-chain protected amide or with an alkylamine togive a side-chain protected alkylamide or dialkylamide. Side-chainprotection is then removed in the usual fashion by treatment withhydrogen fluoride to give the free amides, alkylamides, ordialkylamides.

In preparing the esters of this invention (Y=lower alkoxy), the resinsused to prepare the acids of Formula I (Y=OH) are employed and theside-chain protected group is cleaved with base and the appropriatealcohol, i.e., methanol. Side-chain protection is then removed in theusual fashion by treatment with hydrogen fluoride to obtain the desiredester.

The solid-phase procedure discussed above is well known in the art andhas been essentially described by J. M. Stewart, Solid Phase PeptideSynthesis: (Freeman and Co., San Francisco, 1969).

The compounds of Formula I are useful as analgesics, anti-depressants,tranquilizers, sedatives or hypnotics when administered to mammalianhosts at dosages of from 0.001 to 100 mg/kg of body weight daily,preferably in divided dosages. The compounds are preferably administeredby parenteral routes, i.e., the intravenous, intraperitoneal,intramuscular or subcutaneous routes of administration, but may also beadministered by a variety of other routes including the oral orsublingual, or by vaginal, rectal or nasal routes of administration.Accordingly, one aspect of the present invention includes pharmaceuticalcompositions suitable for such routes of administration.

The analgesic activity of the compounds of Formula I is determined inthe rat tail flick test as described by D'Amour and Smith, J. Pharmac.Exp. Ther., 72, 74 (1941).

The anti-depressant (stimulant) activity and the tranquilizing andsedative-hypnotic activity of the compounds of Formula I is determinedin the open field test described by Kulkarni et al. PharmakopsychiatrieNeuro-Psychopharamkologie 8(1): pp. 45-50 (1975) and the selfstimulation test described by Bailey et al., Research Communications inChemical Pathology and Pharmacology 11(4): pp. 543-552 (1975).

The dosage administered depends upon the desired effect. For example,the degree of analgesia produced by the compounds of this invention maybe varied by varying the dosage. Anti-depressant activity is observed atthe lower dosages, i.e., 0.001 to 5 mg/kg and sedation ortranquilization is produced by dosages of greater than 5 mg/kg of bodyweight.

The following compounds are illustrative of the tripeptides of FormulaI. Compounds of Formula I will hereinafter be designated as β-lipotropinfragment 61-63. The D-amino acid is designated as being in the2-position. Compounds wherein Y-- is OH are named as β-lipotropinfragment 61-63 and are illustrated by the following:

D-ala² -β-lipotropin fragment 61-63;

D-leu² -β-lipotropin fragment 61-63;

D-ile² -β-lipotropin fragment 61-63;

D-val² -β-lipotropin fragment 61-63;

D-phe² -β-lipotropin fragment 61-63;

D-tyr² -β-lipotropin fragment 61-63;

D-trp² -β-lipotropin fragment 61-63;

D-ser² -β-lipotropin fragment 61-63, sodium salt;

D-thr² -β-lipotropin fragment 61-63;

D-met² -β-lipotropin fragment 61-63; calcium salt;

D-glu² -β-lipotropin fragment 61-63;

D-gln² -β-lipotropin fragment 61-63; ammonium salt;

D-asp² -β-lipotropin fragment 61-63;

D-asn² -β-lipotropin fragment 61-63;

D-pro² -β-lipotropin fragment 61-63;

D-lys² -β-lipotropin fragment 61-63;

D-arg² -β-lipotropin fragment 61-63;

The β-lipotropin fragment 61-63 amides of this invention include but arenot limited to the following:

D-ala² -β-lipotropin fragment 61-63 amide;

D-leu² -β-lipotropin fragment 61-63 amide;

D-ile² -β-lipotropin fragment 61-63 amide;

D-val² -β-lipotropin fragment 61-63 amide;

D-phe² -β-lipotropin fragment 61-63 amide;

D-tyr² -β-lipotropin fragment 61-63 amide;

D-trp² -β-lipotropin fragment 61-63 amide;

D-ser² -β-lipotropin fragment 61-63 amide;

D-thr² -β-lipotropin fragment 61-63 amide;

D-met² -β-lipotropin fragment 61-63 amide;

D-glu² -β-lipotropin fragment 61-63 amide;

D-gln² -β-lipotropin fragment 61-63 amide;

D-asp² -β-lipotropin fragment 61-63 amide;

D-asn² -β-lipotropin fragment 61-63 amide;

D-lys² -β-lipotropin fragment 61-63 amide;

D-arg² -β-lipotropin fragment 61-63 amide;

D-ala² -β-lipotropin fragment 61-63 amide hydrochloride;

D-leu² -β-lipotropin fragment 61-63 amide citrate;

D-ile² -β-lipotropin fragment 61-63 amide hydrobromide;

D-val² -β-lipotropin fragment 61-63 amide hydroiodide;

D-phe² -β-lipotropin fragment 61-63 amide hydrochloride;

D-tyr² -β-lipotropin fragment 61-63 amide sulfate;

D-trp² -β-lipotropin fragment 61-63 amide lactate;

D-ser² -β-lipotropin fragment 61-63 amide napsylate;

D-thr² -β-lipotropin fragment 61-63 amide oleate;

D-met² -β-lipotropin fragment 61-63 amide valerate;

D-pro² -β-lipotropin fragment 61-63 amide;

D-glu² -β-lipotropin fragment 61-63 amide tosylate;

D-gln² -β-lipotropin fragment 61-63 amide disulfate;

D-asp² -β-lipotropin fragment 61-63 amide benzoate;

D-asn² -β-lipotropin fragment 61-63 amide acetate;

D-lys² -β-lipotropin fragment 61-63 amide laurate;

D-arg² -β-lipotropin fragment 61-63 amide phosphate;

D-ala² -β-lipotropin fragment 61-63 methylamide;

D-leu² -β-lipotropin fragment 61-63 ethylamide;

D-ile² -β-lipotropin fragment 61-63 propylamide;

D-val² -β-lipotropin fragment 61-63 n-butylamide;

D-phe² -β-lipotropin fragment 61-63 tert-butylamide;

D-tyr² -β-lipotropin fragment 61-63 sec-butylamide;

D-trp² -β-lipotropin fragment 61-63 n-pentylamide;

D-ser² -β-lipotropin fragment 61-63 ethylamide;

D-thr² -β-lipotropin fragment 61-63 dimethylamide;

D-met² -β-lipotropin fragment 61-63 diethylamide;

D-glu² -β-lipotropin fragment 61-63 n-propylamide;

D-gln² -β-lipotropin fragment 61-63 iso-propylamide; and the like.

Esters of this invention include but are not limited to the following:

D-ala² -β-lipotropin fragment 61-63 methyl ester;

D-val² -β-lipotropin fragment 61-63 ethyl ester;

D-met² -β-lipotropin fragment 61-63 n-propyl ester;

D-phe² -β-lipotropin fragment 61-63 iso-propyl ester;

D-glu² -β-lipotropin fragment 61-63 n-butyl ester;

D-gln² -β-lipotropin fragment 61-63 n-pentyl ester;

D-ser² -β-lipotropin fragment 61-63 n-hexyl ester; and the like.

The following examples further illustrate the present invention. In theexamples Nos. 3-98, the intermediates of Formula II are named as theappropriate D-amino acid² -protected β-lipotropin fragment 61-63 resinand the compounds of Formula I are named as the appropriate D-aminoacid² -β-lipotropin fragment 61-63.

EXAMPLE 1 Preparation ofO-2-bromobenzyloxycarbonyl-L-tyrosyl-D-alanyl-glycyl-O-CH₂ -resin(D-Ala² -protected β-lipotropin fragment 61-63.

Tert-butyloxycarbonyl-glycine-O--CH₂ -resin (1.0 mmole), prepared by themethod of Gisin, Helv. Chim. Acta, 56, 1476 (1973) is placed in thereaction vessel of a Beckman Model 990 automatic peptide synthesizer,programmed to carry out the following cycle of washes and reactions: (a)methylene chloride; (b) 25% trifluoroacetic acid in methylene chloride(2 times for 1.5 and 15 minutes each); (c) 50% trifluoroacetic acid inmethylene chloride (15 minutes); (d) methylene chloride; (e) ethanol;(f) methylene chloride; (g) 10% triethylamine in methylene chloride (2times for 5 minutes each); and (h) methylene chloride.

The deprotected resin is then stirred with tert-butyloxycarbonyl (t-Boc)D-alanine (3.0 mmoles) in methylene chloride, anddicyclohexylcarbodiimide (3.0 mmoles) is added thereto. The mixture isstirred at room temperature for 2 hours and the peptide resin is thenwashed successively with methylene chloride, ethanol and methylenechloride. Two percent N-acetylimidazole in methylene chloride is thenadded and the mixture is stirred for 15 minutes in order to irreversiblyacetylate unreacted free amino groups. The resin is then washed withmethylene chloride followed by ethanol and then steps (a) through (h)are repeated as described above.

T-boc-tyrosine is then coupled by the same cycle of events and thecompleted peptide-resin is washed with methanol (3 times) and driedunder reduced pressure to obtain about 5.0 g of the desired material.

EXAMPLE 2 Preparation of L-tyrosyl-D-alanyl-glycine (D-Ala²-β-lipotropin fragment 61-63).

Removal of the protecting groups and cleavage of the peptide from theresin obtained according to the method of Example 1 is carried out bytreating 0.5 mmole of the peptide-resin with hydrogen fluoride (40 ml)and anisole (4 ml) at 0° for 45 minutes. The hydrogen fluoride is thenremoved under reduced pressure and the anisole is removed by washingwith ethyl acetate.

The crude peptide is purified by gel filtration on a column (2.5 × 95cm) of Sephadex G15 gel by elution with 2 molar acetic acid andfractions shown to contain a major peak by uv absorption at 280 nm arepooled and evaporated to dryness. The residual oil is applied to acolumn (2.5 × 95 cm) of Sephadex G25 gel previously equilibrated withthe lower phase followed by the upper phase of a 0.1% acetic acid:n-butanol: pyridine (11:5:3) solvent system. Elution with the upperphase yields a major symmetrical peak, determined by Folin-Lowrymeasurements, and material from this area is evaporated to dryness andlyophilized from water to give the desired product as a powder.

EXAMPLE 3

D-Leu² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-leucine in place of t-BocD-alanine.

EXAMPLE 4

D-Leu² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 3 by the method of Example 2.

EXAMPLE 5

D-Ile² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-isoleucine in place of t-BocD-alanine.

EXAMPLE 6

D-Ile² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of example 5 by the method of Example 2.

EXAMPLE 7

D-Val² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-valine in place of t-BocD-alanine.

EXAMPLE 8

D-Val² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 7 by the method of Example 2.

EXAMPLE 9

D-Phe² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-phenylalanine in place oft-Boc D-alanine.

EXAMPLE 10

D-Phe² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 9 by the method of Example 2.

EXAMPLE 11

O-2-Bromobenzyloxycarbonyl-D-Tyr² -protected β-lipotropin fragment 61-63--O--CH₂ resin is prepared by the method of Example 1, using t-BocD-tyrosine in place of t-Boc D-alanine.

EXAMPLE 12

D-Tyr² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 11 by the method of Example 2.

EXAMPLE 13

D-Trp² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-tryptophan in place of t-BocD-alanine.

EXAMPLE 14

D-Trp² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 13 by the method of Example 2.

EXAMPLE 15

O-Benzyl-D-Ser² -protected β-lipotropin fragment 61-63 --O--CH₂ resin isprepared by the method of Example 1, using t-Boc D-serine in place oft-Boc D-alanine.

EXAMPLE 16

D-Ser² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 15 by the method of Example 2.

EXAMPLE 17

O-Benzyl-D-Thr² -protected β-lipotropin fragment 61-63 --O--CH₂ resin isprepared by the method of Example 1, using t-Boc D-threonine in place oft-Boc D-alanine.

EXAMPLE 18

D-Thr² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 17 by the method of Example 2.

EXAMPLE 19

D-Met² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-methionine in place of t-BocD-alanine.

EXAMPLE 20

D-Met² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 19 by the method of Example 2.

EXAMPLE 21

Gamma-benzyl-D-Glu² -protected β-lipotropin fragment 61-63 --O--CH₂resin is prepared by the method of Example 1, usingt-Boc-gamma-benzyl-D-glutamic acid in place of t-Boc D-alanine.

EXAMPLE 22

D-Glu² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 21 by the method of Example 2.

EXAMPLE 23

Gln² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-glutamine in place of t-BocD-alanine.

EXAMPLE 24

Gln² -β-lipotropin fragment 61-63 is prepared from the protected peptideresin of Example 23 by the method of Example 2.

EXAMPLE 25

α-Benzyl-D-Asp² -protected β-lipotropin fragment 61-63 O--CH₂ -resin isprepared by the method of Example 1, using t-Boc-α-benzyl-D-asparticacid in place of t-Boc D-alanine.

EXAMPLE 26

D-Asp² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 25 by the method of Example 2.

EXAMPLE 27

D-Asn² -protected β-lipotropin fragment 61-63 --O--CH₂ resin is preparedby the method of Example 1, using t-Boc D-asparagine in place of t-BocD-alanine.

EXAMPLE 28

D-Asn² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 27 by the method of Example 2.

EXAMPLE 29

N-epsilon-2-chlorobenzyloxycarbonyl-D-Lys² -protected β-lipotropinfragment 61-63 --O--CH₂ resin is prepared by the method of Example 1,using t-Boc-N-epsilon-2-chlorobenzyloxycarbonyl D-lysine in place oft-Boc D-alanine.

EXAMPLE 30

D-Lys² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 29 by the method of Example 2.

EXAMPLE 31

N-Guanidinotosyl-D-Arg² -protected β-lipotropin fragment 61-63 --O--CH₂-resin is prepared by the method of Example 1, usingt-Boc-N-guanidinotosyl-D-arginine in place of t-Boc D-alanine.

EXAMPLE 32

D-Arg² -β-lipotropin fragment 61-63 is prepared from the protectedpeptide resin of Example 31 by the method of Example 2.

EXAMPLE 33

D-Ala² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared using the conditions described in Example 1, by successivelycoupling the t-Boc derivative of each amino acid to benzhydrylamineresin, purchased from Beckman Instruments, Palo Alto, Calif., instead ofthe O--CH₂ resin employed in Example 1.

EXAMPLE 34

D-Ala² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 33 by the method of Example 2.

EXAMPLE 35

D-Leu² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33 using t-Boc D-leucine in place oft-Boc D-alanine.

EXAMPLE 36

D-Leu² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 35 by the method of Example 2.

EXAMPLE 37

D-Ile² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33, using t-Boc-D-isoleucine in placeof t-Boc-D-alanine.

EXAMPLE 38

D-Ile² -β-lipotropin fragment 61-63 amide is prepared from the resin ofExample 37 by the method of Example 2.

EXAMPLE 39

D-Val² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33, using t-Boc-D-valine in place oft-Boc D-alanine.

EXAMPLE 40

D-Val² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 39 by the method of Example 2.

EXAMPLE 41

D-Phe² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33, using t-Boc-D-phenylalanine inplace of t-Boc-D-alanine.

EXAMPLE 42

D-Phe² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 41 by the method of Example 2.

EXAMPLE 43

2-Bromobenzyloxycarbonyl-D-Tyr² -protected β-lipotropin fragment 61-63benzhydrylamine resin is prepared by the method of Example 33, usingt-Boc-2-bromobenzyloxycarbonyl-D-tyrosine in place of t-Boc D-alanine.

EXAMPLE 44

D-Tyr² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 43 by the method of Example 2.

EXAMPLE 45

D-Trp² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33 using t-Boc D-tryptophan in placeof t-Boc D-alanine.

EXAMPLE 46

D-Trp² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 45 by the method of Example 2.

EXAMPLE 47

O-Benzyl-D-Ser² -protected β-lipotropin fragment 61-63 benzhydrylamineresin is prepared by the method of Example 33 usingt-Boc-O-benzyl-D-serine in place of t-Boc D-alanine.

EXAMPLE 48

D-Ser² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 47 by the method of Example 2.

EXAMPLE 49

O-Benzyl-D-Thr² -protected β-lipotropin fragment 61-63 benzhydrylamineresin is prepared by the method of Example 33, usingt-Boc-O-benzyl-D-threonine in place of t-Boc D-alamine.

EXAMPLE 50

D-Thr² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 49 by the method of Example 2.

EXAMPLE 51

D-Met² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33 using t-Boc D-methionine in placeof t-Boc D-alanine.

EXAMPLE 52

D-Met² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 51 by the method of Example 2.

EXAMPLE 53

D-Glu² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33 using t-Boc-gamma-benzyl-D-glutamicacid in place of t-Boc D-alanine.

EXAMPLE 54

D-Glu² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 53 by the method of Example 2.

EXAMPLE 55

D-Gln² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33 using t-Boc-D-glutamine in place oft-Boc D-alanine.

EXAMPLE 56

D-Gln² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 55 by the method of Example 2.

EXAMPLE 57

α-Benzyl-D-Asp² -protected β-lipotropin fragment 61-63 benzhydrylamineresin is prepared by the method of Example 33 usingt-Boc-α-benzyl-D-aspartic acid in place of t-Boc D-alanine.

EXAMPLE 58

D-Asp² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 57 by the method of Example 2.

EXAMPLE 59

D-Asn² -protected β-lipotropin fragment 61-63 benzhydrylamine resin isprepared by the method of Example 33 using t-Boc D-asparagine in placeof t-Boc D-alanine.

EXAMPLE 60

D-Asn² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 59 by the method of Example 2.

EXAMPLE 61

N-Epsilon-2-chlorobenzyloxycarbonyl-D-Lys² -protected β-lipotropinfragment 61-63 benzhydrylamine resin is prepared by the method ofExample 33 using t-Boc-N-epsilon-2-chlorobenzyloxycarbonyl-D-lysine inplace of t-Boc D-alanine.

EXAMPLE 62

D-Lys² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 61 by the method of Example 2.

EXAMPLE 63

N-guanidinetosyl-D-Arg² -protected β-lipotropin fragment 61-63benzhydrylamine resin is prepared by the method of Example 33, usingt-Boc-N-guanidinetosyl-D-Arginine in place of t-Boc D-alinine.

EXAMPLE 64

D-Arg² -β-lipotropin fragment 61-63 amide is prepared from the protectedpeptide resin of Example 63 by the method of Example 2.

EXAMPLE 65

The methyl ester of D-Ala² -β-lipotropin fragment 61-63 is prepared fromthe protected peptide of Example 1 by cleaving the peptide from theresin with methanol (50 ml) in the presence of triethylamine (40 mmole)at room temperature. Removal of the protecting groups is carried outaccording to the method of Example 2 by treating the peptide withhydrogen fluoride.

EXAMPLE 66

The ethyl ester of D-Leu² -β-lipotropin fragment 61-63 is prepared bythe method of Example 65 from the protected peptide resin of Example 3,using ethanol in place of methanol and conducting the reaction atelevated temperatures.

EXAMPLE 67

The n-propyl ester of D-Ile² -β-lipotropin fragment 61-63 is prepared bythe method of Example 66 from the protected peptide resin of Example 5,using n-propanol instead of ethanol.

EXAMPLE 68

The iso-propyl ester of D-Val² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 7, by the method of Example66, using iso-propanol in place of ethanol.

EXAMPLE 69

The n-butyl ester of D-Phe² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 9, by the method of Example66, using n-butanol instead of ethanol.

EXAMPLE 70

The tert-butyl ester of D-Tyr² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 11 by the method of Example66, using tert-butanol instead of ethanol.

EXAMPLE 71

The sec-butyl ester of D-Trp² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 13 by the method of Example66, using the sec-butanol instead of ethanol.

EXAMPLE 72

The n-pentyl ester of D-Ser² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 15 by the method of Example66, using n-pentanol instead of ethanol.

EXAMPLE 73

The n-hexyl ester of D-Thr² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 17 by the method of Example66, using n-hexanol instead of ethanol.

EXAMPLE 74

The methyl ester of D-Met² -β-lipotropin fragment 61-63 is prepared fromthe protected peptide resin of Example 19 by the method of Example 65.

EXAMPLE 75

The ethyl ester of D-Glu² -β-lipotropin fragment 61-63 is prepared fromthe protected peptide resin of Example 21 by the method of Example 66,using ethanol in place of methanol.

EXAMPLE 76

The 2-methylpentyl ester of D-Gln² -β-lipotropin fragment 61-63 isprepared from the protected peptide resin of Example 23 by the method ofExample 66, using 2-methypentyl alcohol in place of ethanol.

EXAMPLE 77

The 2,3-dimethylbutyl ester of D-Asp² -β-lipotropin fragment 61-63 isprepared from the protected peptide resin of Example 25 by the method ofExample 66, using 2,3-dimethylbutyl alcohol in place of ethanol.

EXAMPLE 78

The iso-propyl ester of D-Asn² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 27 by the method of Example66, using iso-propanol in place of ethanol.

EXAMPLE 79

The n-propyl ester of D-Lys² -β-lipotropin fragment 61-63 is preparedfrom the protected peptide resin of Example 29 by the method of Example66, using n-propanol in place of ethanol.

EXAMPLE 80

The 2,2-dimethylpropyl ester of D-Arg² -β-lipotropin fragment 61-63 isprepared from the protected peptide resin of Example 31 by the method ofExample 66, using 2,2-dimethylpropanol in place of ethanol.

The following examples are illustrative of the preparation of thealkylamides and dialkylamides of this invention.

EXAMPLE 81

D-Ala² -β-lipotropin fragment 61-63 methylamide is prepared by reactingthe peptide resin of Example 1 with a large excess of methylamine indimethylformamide and removal of the side-chain protecting groups of thecleaved methylamide peptide by treatment with hydrogen fluoride in thepresence of anisole under the conditions described in Example 1.

EXAMPLE 82

D-Leu² -β-lipotropin fragment 61-63 ethylamide is prepared from theprotected peptide resin of Example 3 by the method of Example 81 usingethyl amine in place of methyl amine.

EXAMPLE 83

D-Ile² -β-lipotropin fragment 61-63 n-propylamide is prepared from theprotected peptide resin of Example 5 by the method of Example 81, usingn-propyl amine in place of methyl amine.

EXAMPLE 84

D-Val² -β-lipotropin fragment 61-63 n-butylamide is prepared by themethod of Example 81 from the protected peptide resin of Example 7 usingn-butyl amine in place of methyl amine.

EXAMPLE 85

D-Phe² -β-lipotropin fragment 61-63 n-pentylamide is prepared by themethod of Example 81 from the protected peptide resin of Example 9 usingn-pentyl amine in place of methyl amine.

EXAMPLE 86

D-Tyr² -β-lipotropin fragment 61-63 dimethylamide is prepared by themethod of Example 81 from the protected peptide resin of Example 11,using dimethyl amine in place of methyl amine.

EXAMPLE 87

D-Trp² -β-lipotropin fragment 61-63 diethylamide is prepared by themethod of Example 81 from the protected peptide resin of Example 13,using diethyl amine in place of methyl amine.

EXAMPLE 88

D-Ser² -β-lipotropin fragment 61-63 di-n-propyl amide is prepared by themethod of Example 81 from the protected peptide resin of Example 15,using di-n-propyl amine in place of methyl amine.

EXAMPLE 89

D-Thr² -β-lipotropin fragment 61-63 iso-butylamide is prepared by themethod of Example 81 from the protected peptide resin of Example 17,using iso-butylamine in place of methyl amine.

EXAMPLE 90

D-Met² -β-lipotropin fragment 61-63 methylamide hydrochloride isprepared by reacting the free base, prepared by the method of Example 81from the peptide resin of Example 51, with dilute hydrochloric acid.

EXAMPLE 91

D-Glu² -β-lipotropin fragment 61-63 amide oxylate is prepared byreacting the free base of Example 54 with oxalic acid.

EXAMPLE 92

D-Gln² -β-lipotropin fragment 61-63 amide hydroiodide is prepared byreacting the free base of Example 56 with hydroiodic acid.

EXAMPLE 93

D-Asp² -β-lipotropin fragment 61-63 amide citrate is prepared byreacting the free base of Example 58 with citric acid.

EXAMPLE 94

D-Asn² -β-lipotropin fragment 61-63 amide hydrobromide is prepared byreacting the free base of Example 60 with hydrobromic acid.

EXAMPLE 95

D-Lys² -β-lipotropin fragment 61-63 amide sulfate is prepared byreacting the free base of Example 62 with dilute sulfuric acid.

EXAMPLE 96

D-Arg² -β-lipotropin fragment 61-63 amide laurate is prepared byreacting the free base of Example 62 with lauric acid.

EXAMPLE 97

D-Ala² -β-lipotropin fragment 61-63, sodium salt is prepared by reactingthe acid of Example 2 with dilute sodium hydroxide.

It will be apparent to those skilled in the art that Examples 1-97 areillustrative and that any compound of this invention can be preparedfollowing the methods of appropriate Example set forth herein or otherknown solid state peptide synthesis methods.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, at least one of thecompounds of Formula I in association with a pharmaceutical carrier ordiluent. The compounds of this invention can be administered by oral,parenteral (intramuscular, intraperitoneal, intravenous or subcutaneousinjection), nasal, vaginal, rectal or sublingual routes ofadministration and can be formulated in dosage forms appropriate foreach route of administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert diluent such as sucrose,lactose, or starch. Such dosage forms can also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water.Besides, such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring, and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil, andinjectable organic esters such as ethyl oleate. Such dosage forms mayalso contain adjuvants such as preserving, wetting, emulsifying, anddispersing agents. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, by incorporating sterilizing agentsinto the compositions, by irradiating the compositions, or by heatingthe compositions. They can also be manufactured in the form of sterilesolid compositions which can be dissolved in sterile water, or someother sterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as cocoa butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient shall be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment.Generally, dosage levels of between 0.001 to 100 mg/kg. of body weightdaily are administered to mammals to obtain effective relief from painor to relieve depression.

The following examples further illustrate the pharmaceuticalcompositions which are a feature of this invention.

EXAMPLE 98

Tablets weighing 200 mg. and having the following compositions areformulated:

    ______________________________________                                        Ingredient               Mg                                                   ______________________________________                                        D-Ala.sup.2 -β-lipotropin fragment 61-82                                                          50                                                   Starch                   120                                                  Collodial silica         27                                                   Magnesium stearate        3                                                   ______________________________________                                    

EXAMPLE 99

Sterile 10 ml. ampules are prepared containing 10 mg. per ml. of D-Ala²-β-lipotropin fragment 61-63 ethyl ester 0.1 percent sodium bisulfate,0.7 percent sodium chloride and 0.5 percent chlorobutanol as apreservative.

EXAMPLE 100

Topical aqueous formulations for administration by nose drops or nasalspray are formulated containing 1 mg. of D-Ile² -β-lipotropin fragment61-63 amide, 3.8 mgm. glycerine, 40 mg. sorbital, 0.02 mg. benzalkoniumchloride and purified water q.s. 1 m.

EXAMPLE 101

Vaginal suppositories are prepared containing 30 mg. of D-Val²-β-lipotropin fragment 61-63 with lactose in a base made frompolyethylene glycol 400, polysorbate 80, polyethylene glycol 4000,glycerin and butylated hydroxytoluene buffered with lactic acid to anacid pH. The suppositories have an inert covering which dissolvespromptly in the vagina. The covering is composed of gelatin, glycerin,water, methylparaben, propylparaben and coloring.

EXAMPLE 102

Rectal suppositories are prepared by admixing 10 mg. of D-Met²-β-lipotropin fragments 61-63 methyl amide and 2% benzocaine in a basecompounded with polysorbate 80, white beeswax and polypropylene glycolmonostearate.

I claim:
 1. Novel tripeptides represented by the formula

    H-Tyr-X-Gly-X

wherein X is a chiral residue of a D-amino acid selected from the groupconsisting of D-alanine, D-leucine, D-isoleucine, D-valine,D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-histidine,D-proline, D-threonine, D-methionine, D-glutamic acid, D-glutamine,D-aspartic acid, D-asparagine, D-lysine, and D-arginine; Y is selectedfrom the group consisting of hydroxy, amino, loweralkylamino,diloweralkylamino and lower alkoxy; and the pharmaceutically acceptablesalts thereof.
 2. The tripeptides of claim 1 wherein Y is hydroxy. 3.The tripeptides of claim 1 wherein Y is amino.
 4. The tripeptides ofclaim 1 wherein Y is a loweralkylamino.
 5. The tripeptides of claim 1wherein Y is diloweralkylamino.
 6. The tripeptides of claim 1 wherein Yis lower aklkoxy.
 7. Novel tripeptides represented by the formula

    H-Tyr-D-Ala-Gly-Y

wherein Y is selected from the group consisting of hydroxy, amino,loweralkyamino. diloweralkylamine and lower alkoxy; and thepharmaceutically acceptable salts thereof.
 8. The tripeptides of claim 7wherein Y is loweralkylamino.
 9. The tripeptides of claim 7 wherein Y isdiloweralkylamino.
 10. The tripeptides of claim 7 wherein Y is loweralkoxy.
 11. D-Ala² -β-lipotropin fragment 61-63 or a pharmaceuticallyacceptable salt thereof.
 12. D-Ala² -β-liptropin fragment 61-63 amide ora pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition suitable for oral, parenteral, nasal, rectal or vaginal orsublingual administration comprising a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable carrier ordiluent.
 14. A pharmaceutical composition in accordance with claim 13adapted for oral administration.
 15. A pharmaceutical composition inaccordance with claim 13 adapted for parenteral administration.
 16. Apharmaceutical composition in accordance with claim 13 adapted for nasaladministration.
 17. A pharmaceutical composition in accordance withclaim 13 adapted for rectal administration.
 18. A pharmaceuticalcomposition in accordance with claim 13 adapted for vaginaladministration.
 19. A pharmaceutical composition in accordance withclaim 13 adapted for sublingual administration.
 20. Novel tripeptides ofthe formula

    H-Tyr-X'-Gly-Y

wherein X' is a chiral residue of a D-amino acid selected from the groupconsisting of D-alanine, D-leucine, D-isoleucine, D-valine,D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-histidine,D-proline, D-threonine, D-methionine, D-glutamic acid, D-glutamine,D-aspartic acid, D-asparagine, D-lysine and D-arginine with thelimitation that when X' is D-tyrosine, D-threonine, D-serine,D-glutamine, D-lysine, D-aspartic acid or D-arginine, X' is chiral aminoacid residue protected by an R₂, R₃, R₄, R₅, R₆ protecting group; R₁ isa N-terminus solid phase peptide synthesis protecting group selectedfrom the group consisting of acyl-type protecting groups, aromaticurethan-type protecting groups, alkyl-type protecting groups,trialkylsilane groups, or aliphatic urethan protecting groups; R₂ is aprotecting group for the phenolic hydroxyl group of tyrosine selectedfrom the group consisting of tetrahydropyranyl, tert-butyl, trityl,benzyl, 2,4-dichlorobenzyl, benzyloxycarbonyl or2-bromobenzyloxycarbonyl; R₃ is a protecting group for the alcoholhydroxy functions of serine and threonine; R₄ is a protecting group forthe gamma carboxyl group of glutamic acid; R₅ is a protecting group forthe epsilon amino group of lysine selected from the group consisting oftrifluoracetyl, benzyloxycarbonly, and 2-chlorobenzyloxycarbonyl; and R₆is a protecting group for the guanidine group of arginine; R₆ is aprotecting group for the quanidine group of arginine; Y is selected fromthe group consisting of hydroxy, amino, loweralkylamino,diloweralkylamino, or lower alkoxy and a derivatized insolublepolystyrene resin support represented by the formulae ##STR2##